Choline Kinase (ChoK) catalyzes the synthesis of phosphocholine (pCh) as the first step in the metabolic pathway towards synthesis of the major membrane phospholipid, phosphatidylcholine.
The choline kinase family is encoded by two separate genes, CHKα and CHKβ, resulting in three different proteins with variable choline/ethanolamine kinase (ChoK/EtnK) activity, namely, ChoKα1, ChoKα2 and ChoKβ1. Both ChoKα1 and ChoKα2 preferentially phosphorylate choline over ethanolamine, compared to ChoKβ.
ChoKα1 is a 457 amino acid polypeptide provided in the NCBI database under accession number NP 001268 (release of Jun. 17, 2012). The polypeptide is encoded by a 2733 base-pair (bp) transcript formed by alternative splicing from the ChoKα gene. The cDNA sequence of the transcript encoding ChoKα1 is provided in the NCBI database with accession number NM_001277 (release of Jun. 17, 2012).
ChoKα2 is a 439 amino acid polypeptide provided in the NCBI database under accession number NP 997634 (release of Jun. 17, 2012). The polypeptide is encoded by a 2679 bp transcript formed by alternative splicing from the ChoKα gene. The cDNA sequence of the transcript encoding ChoKα2 is provided in the NCBI database with accession number M_M 212469 (release of Jun. 17, 2012).
Abnormal choline metabolism is characteristic of oncogenesis and cancer progression in an array of cancer types. Exogenous expression of ChoKα1, but not ChoKβ1, is capable of driving tumor formation in non-transformed cells (Gallego-Ortega et al., PLoS One, 2009). It is known that increased phosphorylation of choline is a hallmark of certain malignant phenotypes. ChoK over-expression, (primarily ChoKα1), has been associated with certain human cancers, including breast, liver, lung, colorectal, ovary and prostate (Glunde et al. Nat Rev Can, 2011). For example, ChoKα, phosphocholine and total choline were increased in breast carcinomas compared with normal breast tissue, and this increase correlated with advanced tumor grade (Ramirez de Molina et al., Oncogene, 2002; Gribbestad et al., Anticancer Res, 1999). This finding suggests that any tumor type that displays elevated pCho or ChoK itself would be a candidate for ChoK inhibitor therapy.
In addition to tumor type, there is preclinical evidence that inhibition of ChoK expression in cell lines results in disruption of MAPK and AKT activity and decreased cell proliferation (Yalcin, et al. Oncogene, 2009; Clem et al. Oncogene, 2011). It has also been found that cell lines expressing activated RAS exhibit sensitivity to ChoK knockdown by siRNA or small molecule inhibition (Ramirez de Molina et al. Biochem Biophys Res Commun, 2001). These studies indicate that tumors demonstrating aberrant MAPK, AKT or RAS signaling may be used as a general target for ChoK anticancer drug design.
These observations have motivated efforts to develop anti-cancer agents targeting ChoK.